The present invention relates generally to processes for the asymmetric synthesis of amino-pyrrolidinones, such pyrrolidinones being useful as intermediates for MMP and TACE inhibitors.
Amino-pyrrolidinones of the type shown below are currently being studied as MMP and TACE inhibitors in clinical settings. As one of ordinary skill in the art understands, clinical trials and NDA submissions require practical, large-scale synthesis of the active drug. 
Consequently, it is desirable to find new synthetic procedures for making amino-pyrrolidinones.
Accordingly, the present invention provides a novel intermediate for making an amino-pyrrolidinone.
The present invention provides a novel amino-pyrrolidinone.
The present invention provides a novel process for making amino-pyrrolidinones.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that novel compounds of formula II can be formed from novel compounds of formula I. 
Thus, in an embodiment, the present invention provides a novel process of forming a compound of formula II, comprising: 
(a) contacting a compound of formula I with a strong base in the presence of a first solvent, wherein the first solvent is an aprotic solvent;
(b) contacting the resulting solution from (a) with an aminating reagent, wherein the aminating reagent is an electrophilic nitrogen source; and,
(c) if necessary, treating the amination product of (b) by reducing, hydrolyzing, or a combination thereof to form a compound of formula II;
wherein:
Rf is absent;
Ry is selected from H, OH, C1-6 alkyl, and C3-12 cycloalkyl;
Rz is selected from H, C1-6 alkyl, and C3-12 cycloalkyl;
alternatively, Rf is O, Rz is absent, and Ry forms a C3-12 cycloalkyl group double bonded to the nitrone nitrogen or is a carbon atom double bonded to the nitrone nitrogen and substituted with R6 and R7;
R6 is C1-6 alkyl or C3-12 cycloalkyl;
R7 is C1-6 alkyl or C3-12 cycloalkyl;
R1 is Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
Z is phenyl or pyridyl substituted with 1-5 Rb;
Ua is absent or is selected from O and NRa;
Xa is absent or is selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or is selected from O and NRa;
Za is selected from H, C3-13 carbocyclic residue substituted with 0-5 Rc, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0-5 Rc;
R2 is H;
R3 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRx)r1O(CRRx)rxe2x80x94Q, and (CRRx)r1NRa(CRRx)rxe2x80x94Q;
Q is selected from H and a C3-13 carbocyclic residue substituted with 0-5 Rd;
R, at each occurrence, is independently selected from H, CH3, CH2CH3, CHxe2x95x90CH2, CHxe2x95x90CHCH3, and CH2CHxe2x95x90CH2;
Rx, at each occurrence, is independently selected from H, CH3, CH2CH3, and CH(CH3)2;
R4 is selected from H, C1-10 alkylene-H, C2-10 alkenylene-H, C2-10 alkynylene-H, (CRRx)r1O(CRRx)rxe2x80x94H, and (CRRx)r1NRa(CRRx)rxe2x80x94H;
alternatively, R3 and R4 combine to form a C3-13 carbocyclic residue substituted with R4a and 0-3 Rb;
R4a is Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
R5 is selected from H, C1-6 alkyl, phenyl, and benzyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, and benzyl;
Ra1, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, and benzyl;
Ra2, at each occurrence, is independently selected from H, C1-4 alkyl, benzyl, C3-7 carbocyclic residue, and a 5 to 6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, Ra and Ra1 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, CN, NRaRa1, S(O)2NRaRa1, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, F, NRaRa1, CF3, and CF2CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, F, NRaRa1, S(O)2NRaRa1, CF3, and CF2CF3;
n is selected from 0, 1, 2, and 3;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; and,
rl, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5.
In a preferred embodiment, the present invention provides a novel process, wherein (c) is performed by reducing the amination product from (b) to form a compound of formula II, wherein:
Ry is selected from H, C1-6 alkyl, and C3-12 cycloalkyl; and,
Rz is selected from H, C1-6 alkyl, and C3-12 cycloalkyl.
In another preferred embodiment, the present invention provides a novel process, wherein (a) is performed in the presence of an inorganic salt selected from a lithium salt, a potassium salt, and a sodium salt; and (c) is performed by contacting the amination product from (b) with a reducing agent and an acid;
the compound of formula I is the compound of formula Ia: 
the compound of formula II is a compound of formula IIa: 
the strong base is selected from an alkyl lithium, lithium amide, hydride base, and an organometallic base;
the first solvent is selected from an ethereal solvent, a hydrocarbon solvent, and an aromatic hydrocarbon solvent;
the aminating reagent is selected from a chloro-nitroso compound, a sulfonyl azide, a nitroso compound, an azodicarboxylate, a sulfonamide, and an oxaziridine compound;
the reducing agent is selected from zinc and iron;
the acid is selected from formic acid, acetic acid, and methanesulfonic acid;
wherein:
Ry is H;
Rz is H;
Ua is absent or is O;
Xa is absent or is C1-4 alkylene;
Ya is absent;
Za is selected from H, C5-6 carbocyclic residue substituted with 0-2 Rc, and a 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0-2 Rc; and,
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, NRaRa1, and CF3;
Rc, at each occurrence, is independently selected from C1-4 alkyl, ORa, F, NRaRa1, and CF3; and,
R5 is H or C1-6 alkyl.
In another preferred embodiment, the present invention provides a novel process, wherein (b) is performed in the presence of a second solvent and the second solvent is an aprotic solvent;
the inorganic salt is selected from lithium chloride, lithium perchlorate, lithium bromide, lithium iodide, potassium chloride, potassium bromide, potassium iodide, sodium chloride, sodium bromide, and sodium iodide;
the strong base is selected from methyl lithium, ethyl lithium, n-propyl lithium, i-propyl lithium, n-butyl lithium, i-butyl lithium, s-butyl lithium, t-butyl lithium, hexyl lithium, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, potassium bis(trimethylsilyl)amide, potassium hydride, and sodium hydride;
the first solvent is selected from tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether, and dimethoxymethane;
the second solvent is selected from tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether, dimethoxymethane, and toluene;
the aminating reagent is selected from 1-chloro-1-nitrosocyclopentane, 1-chloro-1-nitrosocyclohexane, and 2-chloro-2-nitrosopropane;
the reducing agent is zinc;
wherein:
Ua is O;
Xa is absent or is CH2;
Za is H or phenyl; and,
R5 is H or CH3.
In another preferred embodiment, the present invention provides a novel process, wherein:
the inorganic salt is selected from lithium chloride and lithium perchlorate;
the strong base is selected from n-butyl lithium and hexyl lithium;
the first solvent is selected from tetrahydrofuran and 1,2-dimethoxyethane;
the second solvent is toluene; and,
the aminating reagent is selected from 1-chloro-1-nitrosocyclopentane and 1-chloro-1-nitrosocyclohexane.
In another preferred embodiment, the present invention provides a novel process, wherein:
the inorganic salt is lithium chloride;
the strong base is n-butyl lithium;
the first solvent is tetrahydrofuran;
the second solvent is toluene;
the aminating reagent is 1-chloro-1-nitrosocyclopentane; and,
the acid is formic acid.
In another preferred embodiment, the present invention provides a novel process, wherein (c) further comprises:
(c1) esterifying the acid product from b1, wherein:
R5 is C1-6 alkyl.
In another preferred embodiment, the present invention provides a novel process, wherein in (c1) the esterification is performed by contacting the reduced product with an acid in the presence of an alcohol.
In another preferred embodiment, the present invention provides a novel process, wherein the acid is methanesulfonic acid and the alcohol is methyl alcohol.
In another preferred embodiment, the present invention provides a novel process, further comprising:
(d) subjecting the compound from (c) wherein Ry is OH to catalytic hydrogenation with a noble metal catalyst to form a compound of formula II wherein Ry is H.
In another preferred embodiment, the present invention provides a novel process, wherein the noble metal catalyst is palladium.
In another embodiment, the present invention provides a novel compound of formula IIb: 
wherein:
Rz is absent and Ry forms a C3-12 cycloalkyl group double bonded to the nitrone nitrogen or is a carbon atom double bonded to the nitrone nitrogen and substituted with R6 and R7;
R6 is C1-6 alkyl or C3-12 cycloalkyl;
R7 is C1-6 alkyl or C3-12 cycloalkyl;
R1 is Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
Z is phenyl or pyridyl substituted with 1-5 Rb;
Ua is absent or is selected from O and NRa;
Xa is absent or is selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or is selected from O and NRa;
Za is selected from H, C3-13 carbocyclic residue substituted with 0-5 Rc, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0-5 Rc;
R2 is H;
R3 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRx)r1O(CRRx)rxe2x80x94Q, and (CRRx)r1NRa(CRRx)rxe2x80x94Q;
Q is selected from H and a C3-13 carbocyclic residue substituted with 0-5 Rd;
R, at each occurrence, is independently selected from H, CH3, CH2CH3, CHxe2x95x90CH2, CHxe2x95x90CHCH3, and CH2CHxe2x95x90CH2;
Rx, at each occurrence, is independently selected from H, CH3, CH2CH3, and CH(CH3)2;
R4 is selected from H, C1-10 alkylene-H, C2-10 alkenylene-H, C2-10 alkynylene-H, (CRRx)r1O(CRRx)rxe2x80x94H, and (CRRx)r1NRa(CRRx)rxe2x80x94H;
alternatively, R3 and R4 combine to form a C3-13 carbocyclic residue substituted with R4a and 0-3 Rb;
R4a is Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
R5 is selected from H, C1-6 alkyl, phenyl, and benzyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, and benzyl;
Ra1, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, and benzyl;
Ra2, at each occurrence, is independently selected from H, C1-4 alkyl, benzyl, C3-7 carbocyclic residue, and a 5 to 6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, Ra and Ra1 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, CN, NRaRa1, S(O)2NRaRa1, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, F, NRaRa1, CF3, and CF2CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, F, NRaRa1, S(O)2NRaRa1, CF3, and CF2CF3;
n is selected from 0, 1, 2, and 3;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5.
In another preferred embodiment, the present invention provides a novel compound, wherein the compound is of formula IIc: 
wherein:
Rz is absent and Ry forms a cyclobutyl, cyclopentyl, or cyclohexyl group double bonded to the nitrone nitrogen;
Ua is absent or is O;
Xa is absent or is C1-4 alkylene;
Ya is absent;
Za is selected from H and phenyl; and,
R5 is H or C1-6 alkyl.
In another preferred embodiment, the present invention provides a novel compound of formula IId: 
In another preferred embodiment, the present invention provides a novel compound of the formula: 
wherein the compound is present in its HCl salt form.
In another preferred embodiment, the present invention provides a novel compound of the formula: 
The present invention can be practiced on multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferable in the scale wherein at least one starting material is present in 10 grams or more, more preferable at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilo of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory sale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention may contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
As used herein, equivalents are intended to mean molar equivalents unless otherwise specified.
The reactions of the synthetic methods claimed herein are carried out in suitable solvents which may be readily selected by one of skill in the art of organic synthesis, the suitable solvents generally being any solvent which is substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which may range from the solvent""s freezing temperature to the solvent""s boiling temperature. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected.
Suitable polar solvents include, but are not limited to, ether and aprotic solvents.
Suitable ether solvents include: dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, 1,2-dimethoxyethane, diethoxymethane, dimethoxymethane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.
Suitable aprotic solvents may include, by way of example and without limitation, ether solvents, tetrahydrofuran (THF), dimethylformamide (DMF), 1,2-dimethoxyethane, diethoxymethane, dimethoxymethane, dimethylacetamide (DMAC), benzene, toluene, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.
Suitable hydrocarbon solvents include, but are not limited to, benzene, cyclohexane, pentane, hexane, hexanes, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-xylene, o-xylene, p-xylene, octane, indane, nonane, or naphthalene.
As used herein, an alcohol solvent is a hydroxy-substituted compound that is liquid at the desired temperature (e.g., room temperature). Examples of alcohols include, but are not limited to, methyl alcohol, ethyl alcohol, n-propanol, and i-propanol.
As used herein, the term xe2x80x9camino protecting groupxe2x80x9d (or xe2x80x9cN-protectedxe2x80x9d) refers to any group known in the art of organic synthesis for the protection of amine groups. As used herein, the term xe2x80x9camino protecting group reagentxe2x80x9d refers to any reagent known in the art of organic synthesis for the protection of amine groups that may be reacted with an amine to provide an amine protected with an amine-protecting group. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York, (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl (TFA), phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (cbz) and substituted benzyloxycarbonyls, 2-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyloxycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolylmethyloxycrbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycrbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; Nxe2x80x2-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; and methanesulfonamide.
As used herein, the term xe2x80x9cnoble metal catalystxe2x80x9d refers to noble metals, known in the art of organic synthesis, used in catalytic hydrogenation. Examples of noble metal catalysts include, but are not limited to, palladium or platinum.
Preferably, the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 grams per mole. More preferably, the molecular weight is less than about 950 grams per mole. Even more preferably, the molecular weight is less than about 850 grams per mole. Still more preferably, the molecular weight is less than about 750 grams per mole.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-6 alkyl, is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Alkenylxe2x80x9d is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C2-6 alkenyl is intended to include C2, C3, C4, C5, and C6 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C2-6 Alkynyl is intended to include C2, C3, C4, C5, and C6 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
By way of example and without limitation, the present invention may be further understood by the following schemes and descriptions. Scheme 1 exemplifies how a desired end product can be formed using the presently claimed process and intermediates. 
Starting Material: 2-(4-Benzyloxy-phenyl)-pent-4-enoic acid methyl ester can be prepared by alkylating 2-(4-benzyloxy-phenyl)-ethanoic acid methyl ester. The starting ester is deprotonated with a strong base and then alkylated with an allyl alkylating reagent. Preferably, the base is selected from lithium diisopropylamide, lithium hexamethyldisilamide, as well as other lithium bases. More preferably, the base is lithium diisopropylamide or lithium hexamethyldisilamide. Even more preferably, the base is lithium diisopropylamide. Preferably from 0-9 to 1.2 equivalents of base are used, more preferably 1.1. The allyl alkylating agent is preferably allyl bromide or allyl chloride, with allyl bromide being more preferred. Preferably, 0.9 to 2 equivalents of alkylating agent are use, more preferably 1.3. An aprotic solvent is preferably used. Preferred solvents include tetrahydrofuran, dimethylformamide, and diethoxymethane, with tetrahydrofuran being more preferred.
Reaction 1: Compound A can be formed by methods known to those of skill in the art of organic synthesis. For example, it can be formed by subjecting the shown compound to ozonolysis and then quenched. Preferably 1-2 equivalents of ozone are used, more preferably 1. Preferably, the ozonolysis is quenched with Zn. From 1-5 equivalents of Zn are preferred with 2 being more preferred. Generally, an acid is also used to quench the reaction. Preferably, the acid is acetic acid. Other work-ups include using dimethyl sulfide, triphenyl phosphine, and other phosphines known to those of ordinary skill in the art. Solvents including ethyl acetate and methylene chloride can be used. Ethyl acetate is preferred. Compound A need not be a benzyl-protected hydroxy-phenyl moiety. It could be one of numerous starting materials depending on the desired end product, Compound F.
Reaction 2: Lactam B can then be formed by methods known to those of skill in the art of organic synthesis. For example, compound A can be treated with a protected (e.g., methyl ester) amino acid under reductive amination conditions (e.g., NaBH(OAc)3), cyclized to the lactam by heating, and the resulting product deprotected (e.g., LiOH). The protected amino acid used in this sequence will depend in the desired product. One of ordinary skill in the art would recognize that numerous different protected amino acids could be effectively used in this reaction.
Reaction 3: Reaction 3 generally involves two or three reactions: (a) deprotonating compound B, (b) contacting the resulting product with an aminating reagent, and, if desired, (c) converting the resulting intermediate to an amino group (Compound C2) or a hydroxylamine (Compound C1).
Reaction 3(a): Compound B is contacted with a strong base (e.g., n-BuLi) in the presence of a first solvent, wherein the first solvent is an aprotic solvent (e.g., THF). Preferably, the strong base is an alkyl lithium, lithium amide, hydride base, or other organometallic bases. More preferably, the strong base is methyl lithium, ethyl lithium, n-propyl lithium, i-propyl lithium, n-butyl lithium, i-butyl lithium, s-butyl lithium, t-butyl lithium, hexyl lithium, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, potassium bis(trimethylsilyl)amide, potassium hydride, or sodium hydride. Even more preferably, the strong base is n-butyl lithium or hexyl lithium. Still more preferably, the strong base is n-butyl lithium.
Preferably, the first solvent, an aprotic solvent, is an ethereal solvent, a hydrocarbon solvent, or an aromatic hydrocarbon solvent. More preferably, the first solvent is tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether, or dimethoxymethane. Even more preferably, the first solvent is tetrahydrofuran or 1,2-dimethoxyethane. Most preferably, the first solvent is tetrahydrofuran.
Reaction 3(a) is advantageously performed in the presence of an inorganic salt that is a lithium salt, a potassium salt, or a sodium salt. More preferably, the salt is lithium chloride, lithium perchlorate, lithium bromide, lithium iodide, potassium chloride, potassium bromide, potassium iodide, sodium chloride, sodium bromide, or sodium iodide. Even more preferably, the salt is lithium chloride or lithium perchlorate. Still more preferably, the salt is lithium chloride.
Reaction 3(b): Reaction 3(b) involves the addition of an a chiral aminating reagent diastereoselectively provide the tetra-substituted carbon. The resulting solution from (a) is contacted with an aminating reagent, wherein the aminating reagent is an electrophilic nitrogen source (e.g., 1-chloro-1-nitrosocyclopentane). Preferably, the aminating reagent is a chloro-nitroso compound, a sulfonyl azide, a nitroso compound, an azodicarboxylate, a sulfonamide, or an oxaziridine compound. More preferably, the aminating reagent is 1-chloro-1-nitrosocyclopentane, 1-chloro-1-nitrosocyclohexane, or 2-chloro-2-nitrosopropane. Even more preferably, the aminating reagent is 1-chloro-1-nitrosocyclopentane or 1-chloro-1-nitrosocyclohexane. Still more preferably, the aminating reagent is 1-chloro-1-nitrosocyclopentane.
Reaction 3(b) is preferably performed in the presence of a second solvent, preferably an aprotic solvent. More preferably, the second solvent is tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether, dimethoxymethane, benzene, and toluene. Even more preferably, the second solvent is benzene and toluene. Still more preferably, the second solvent is toluene.
The compound resulting from reaction 3(b) has two sterocenters. Preferably, the diastereoselectivity (i.e., de) is 10:1, more preferably 11:1, and even more preferably 13:1.
Reaction 3(c): After amination of Compound B, an aminated product is formed. In a preferred an embodiement the aminated product is a nitrone. The nitrone can be hydrolyzed to a hydroxylamine or reduced to an amino group depending on how it is treated. It is preferable to convert this nitrone to an amino group and esterify the acid group (Compound C2).
The nitrone is reduced to an imine group by the addition of a reducing agent and concomitant hydrolysis and/or alcoholysis affords the amino group (e.g., zinc in the presence of an acid and an alcohol or water). A preferred reducing agent is zinc. Preferred acids used in conjunction with the reducing agent (i.e., zinc) include, but are not limited to, methanesulfonic acid, acetic acid, formic acid, hydrochloric acid, and sulfuric acid. A preferred combination is zinc and formic acid.
Esterification of the amino-acid resulting from nitrone reduction can be accomplished by methods known to those of ordinary skill in the art (i.e., addition of an acid and an alcohol). Esters that can be formed included, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, and benzyl. A preferred ester is an alkyl ester. A more preferred ester is methyl ester. Preferably, the methyl ester is formed by the addition of methyl alcohol and methanesulfonic acid. Other acids can be used, such as acetic acid, hydrochloric acid, and sulfuric acid.
The hydroxylamine group is generally obtained by treatment with water and an acid (e.g. methanesulfonic acid, citric acid, or formic acid). It is preferred to conduct this conversion in an alcoholic solvent (e.g., methyl alcohol). The hydroxylamine group can be converted to an amino group by methods known to those of ordinary skill in the art. For example, the hydroxylamine can be reduced to an amino group by the addition of a reducing agent (e.g., zinc in the presence of an acid). A preferred reducing agent is zinc. Preferred acids used in conjunction with the reducing agent (i.e., zinc) include, but are not limited to, methanesulfonic acid, acetic acid, formic acid, hydrochloric acid, and sulfuric acid. A preferred combination is zinc and formic acid.
Reaction 4: Reaction 4 depends on the desired end product, the protecting groups used, and the aminating reagent used. Certain selections of the end product, protecting groups, and aminating reagents can obviate the need for Reaction 4. As shown in Scheme 1, Reaction 4 involves deprotecting the hydroxyl group and, optionally, if the hydroxylamine is present, simultaneously converting it to an amine. The hydroxyl group can be deprotected and the hydroxylamine, if present, simultaneously converted to the amine by methods known to those of ordinary skill in the art. For example, the benzyl group can be removed and the hydroxylamine, if present, can be simultaneously converted to the amine by hydrogenation in the presence of a catalyst (e.g., Pd/C) and a solvent (e.g., methyl alcohol).
Reaction 5: Reaction 5 will depend on the desired end product as well as the protecting groups and aminating agents previously used. As shown in Scheme 1, Reaction 5 can involve treating compound D with a molecule having an appropriate leaving group (e.g., 4-chloromethyl-2-methyl-quinoline). It may also be useful to protect the free amine. For example, Compound D can be treated with an amine protecting agent (e.g., p-tolualdehyde under water removing conditions) and the resulting imine then treated with a molecule having an appropriate leaving group.
Compound E is preferably isolated as a salt. Preferred salts of E include methanesulfonic acid and hydrochloric acid. The hydrochloric acid salt is more preferred.
Reaction 6: Reaction 6 involves replacing the methoxy group with a hydroxylamine group. Suitable hydroxylamines include hydroxylamine hydrochloride and hydroxylamine sulfate. Preferably, hydroxylamine hydrochloride is used. From 1-10 equivalents of hydroxylamine are preferably used. More preferably, 5 equivalents of hydroxylamine are used. Alcohols such as methyl alcohol, t-amyl alcohol, and t-butyl alcohol can be used, methyl alcohol being preferred.
Examples of electrophilic nitrogen sources:
1) Nitrenoids of the type MRNxe2x80x94ORxe2x80x2 (M=metal): 
2) Azocarboxylates of the type RCO2Nxe2x95x90NCO2R: 
3) Sulfonylazides of the type RSO2N3: 
4) Oxaziridines of the type RCONR1: 
Alternative methods of making the lactam cores of the present invention are shown below. 
The present invention also includes the novel use of a 1-chloro-1-nitrosocyclopentane solution. 
Reagents for preparing chloronitroso reagents: Cl2, nitrosyl chloride (PhSO2NCl2), alkyl-hypochlorite (tBuOCl), aqueous hypochlorous acid, hypochlorous acid/(1R)-isobornyl ester, NOCl, and N,Nxe2x80x2-dichloro-N,Nxe2x80x2-dinitro-ethylenediamine.
Solvents for preparing chloronitroso reagents: diethyl ether, benzene, cyclohexane, water, acetic acid, concentrated hydrochloric acid, toluene and ethyl acetate or similar solvents or mixtures thereof.
Halogenated solvents include: CCl3F, CH2Cl2, CHCl3, CCl4.
Other features of the invention will become apparent in the course of the following descriptions of examplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.